CHEMISTRY AND BIOLOGY OF PLATINUM ANTICANCER DRUGS
铂类抗癌药物的化学和生物学
基本信息
- 批准号:7955152
- 负责人:
- 金额:$ 0.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-04-01 至 2010-03-31
- 项目状态:已结题
- 来源:
- 关键词:Antineoplastic AgentsBase PairingBiologyChemistryCisplatinColorectal CancerComplexComputer Retrieval of Information on Scientific Projects DatabaseDNADNA AdductsDNA StructureDataFundingGenetic TranscriptionGrantInstitutionLeftLesionMajor GrooveModelingMolecular ConformationMolecular Mechanisms of ActionMusPlatinumPlatinum CompoundsProteinsResearchResearch PersonnelResourcesSideSiteSourceStructural ModelsStructure-Activity RelationshipUnited States National Institutes of HealthWorkX ray diffraction analysisX-Ray Diffractionadductantitumor agentcrosslinkcytotoxicityin vivointerestpyridinerepairedstructural biologytumor
项目摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
The platinum compound cis-[Pt(NH3)2(pyridine)Cl]Cl has previously demonstrated potent cytotoxicity in a screen against in vivo murine tumor models. This result is of particular interest because this compound forms only monofunctional adducts with DNA, and thus does not follow the classic structure-activity relationship for platinum anti-tumor agents that requires two leaving groups to be present in a cis conformation. Recent data has shown this compound may be recognized by cellular repair proteins and block transcription in a manner that is unique to monofunctional platinum compounds, but similar to cisplatin and other bifunctional platinum compounds. It is therefore desirable to obtain a detailed structural model of this platinum-DNA adduct, which may help to explain the unexpected activity of the complex. We have recently crystallized a DNA dodecamer duplex containing a single {Pt(NH3)2(pyridine)}-dG adduct, and collected X-ray diffraction data to 2.17 ¿. The global structure of the DNA is quite different from that of DNA containing a platinum intrastrand d(GpG) cross-link. The latter platinated duplex is bent by ~40¿ towards the major groove at the site of the cross-link, yet the monofunctional platinumdG lesion causes no significant distortion of the double helix. Like the cisplatin intrastrand cross-link, however, the monofunctional adduct creates a distorted base pair step to the 5' side of the platinum site that may be correlated to antitumor activity. These data allow us to reevaluate the structure-activity relationship of platinum anticancer agents to include monofunctional, "non-classical" platinum compounds, and to use this evidence to work towards elucidating the molecular mechanism of action of a unique platinum complex that may be able to be used in treatment of colorectal cancer.
这个子项目是许多研究子项目中利用
资源由NIH/NCRR资助的中心拨款提供。子项目和
调查员(PI)可能从NIH的另一个来源获得了主要资金,
并因此可以在其他清晰的条目中表示。列出的机构是
该中心不一定是调查人员的机构。
铂化合物顺式-[铂(NH3)2(吡啶)氯]氯先前已显示出强大的细胞毒性在筛选中对小鼠体内肿瘤模型。这一结果特别令人感兴趣,因为这种化合物只与DNA形成单功能加合物,因此不符合铂抗肿瘤药物的经典构效关系,即需要两个离开基团以顺式构象存在。最近的数据表明,这种化合物可能被细胞修复蛋白识别,并以一种单功能铂化合物特有的方式阻断转录,但类似于顺铂和其他双功能铂化合物。因此,需要获得这种铂-DNA加合物的详细结构模型,这可能有助于解释该络合物的意外活性。我们最近结晶了一个含有单一的{PT(NH3)2(吡啶)}-DG加合物的DNA十二聚体双链,并收集了2.17的X射线衍射数据。DNA的全局结构与含有铂链D(GPG)交联物的DNA有很大的不同。后者的铂双链向交联处的主槽弯曲约40°,而单功能铂双螺旋损伤并未引起明显的双螺旋扭曲。然而,与顺铂链内交联物一样,单功能加合物在铂位置的5‘侧产生了一个扭曲的碱基对步骤,这可能与抗肿瘤活性有关。这些数据使我们能够重新评估铂抗癌剂的构效关系,包括单官能团、非经典的铂化合物,并利用这一证据来努力阐明一种独特的铂络合物的分子作用机制,该络合物可能能够用于治疗结直肠癌。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Stephen J. Lippard其他文献
X-ray structure of a dodecamer duplex containing the major cisplatin d(GpG) intrastrand cross-link
- DOI:
10.1016/0162-0134(95)97300-f - 发表时间:
1995-08-01 - 期刊:
- 影响因子:
- 作者:
Patricia M. Takahara;Amy C. Rosenzweig;Christin A. Frederick;Stephen J. Lippard - 通讯作者:
Stephen J. Lippard
Frank Albert Cotton (1930–2007)
弗兰克·艾伯特·科顿(1930 年至 2007 年)
- DOI:
10.1038/446626a - 发表时间:
2007-04-04 - 期刊:
- 影响因子:48.500
- 作者:
Stephen J. Lippard - 通讯作者:
Stephen J. Lippard
High resolution crystal structures of the hydroxylase protein of methane monooxygenase
- DOI:
10.1016/0162-0134(95)97479-a - 发表时间:
1995-08-01 - 期刊:
- 影响因子:
- 作者:
Amy C. Rosenzweig;Pär Nordlund;Stephen J. Lippard;Christin A. Frederick - 通讯作者:
Christin A. Frederick
Conjugués de nanoparticule de polynucléotide polyvalente en tant que véhicules de distribution pour un agent chimiothérapique
多核苷酸多价纳米粒子结合物与化学药物分配载体
- DOI:
- 发表时间:
2010 - 期刊:
- 影响因子:0
- 作者:
Chad A. Mirkin;David A. Giljohann;W. Daniel;Stephen J. Lippard;Shanta Dhar - 通讯作者:
Shanta Dhar
Structural, mechanistic, and model studies for methane monooxygenase
- DOI:
10.1016/0162-0134(95)97192-s - 发表时间:
1995-08-01 - 期刊:
- 影响因子:
- 作者:
Stephen J. Lippard - 通讯作者:
Stephen J. Lippard
Stephen J. Lippard的其他文献
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{{ truncateString('Stephen J. Lippard', 18)}}的其他基金
STRUCTURAL STUDIES OF BACTERIAL MULTICOMPONENT MONOOXYGENASES
细菌多组分单加氧酶的结构研究
- 批准号:
8362193 - 财政年份:2011
- 资助金额:
$ 0.22万 - 项目类别:
INVESTIGATIONS OF CISPLATIN-DNA CROSS-LINKS ON NUCLEOSOME CORE PARTICLES
核小体核心颗粒上顺铂-DNA 交联的研究
- 批准号:
8169250 - 财政年份:2010
- 资助金额:
$ 0.22万 - 项目类别:
STRUCTURAL STUDIES OF BACTERIAL MULTICOMPONENT MONOOXYGENASES
细菌多组分单加氧酶的结构研究
- 批准号:
8170154 - 财政年份:2010
- 资助金额:
$ 0.22万 - 项目类别:
STRUCTURAL STUDIES OF MULTICOMPONENT BACTERIAL MONOOXYGENASES
多组分细菌单加氧酶的结构研究
- 批准号:
8169251 - 财政年份:2010
- 资助金额:
$ 0.22万 - 项目类别:
STRUCTURAL STUDIES OF BACTERIAL MULTICOMPONENT MONOOXYGENASES
细菌多组分单加氧酶的结构研究
- 批准号:
7954158 - 财政年份:2009
- 资助金额:
$ 0.22万 - 项目类别:
Nonheme Diiron Centers and the Biological Oxidation of Hydrocarbons
非血红素二铁中心和碳氢化合物的生物氧化
- 批准号:
7923548 - 财政年份:2009
- 资助金额:
$ 0.22万 - 项目类别:
STRUCTURAL STUDIES OF BACTERIAL MULTICOMPONENT MONOOXYGENASES
细菌多组分单加氧酶的结构研究
- 批准号:
7954496 - 财政年份:2009
- 资助金额:
$ 0.22万 - 项目类别:
STRUCTURAL STUDIES OF MULTICOMPONENT BACTERIAL MONOOXYGENASES
多组分细菌单加氧酶的结构研究
- 批准号:
7955153 - 财政年份:2009
- 资助金额:
$ 0.22万 - 项目类别:
STRUCTURAL STUDIES OF BACTERIAL MULTICOMPONENT MONOOXYGENASES
细菌多组分单加氧酶的结构研究
- 批准号:
7721732 - 财政年份:2008
- 资助金额:
$ 0.22万 - 项目类别:
STRUCTURAL STUDIES OF BACTERIAL MULTICOMPONENT MONOOXYGENASES
细菌多组分单加氧酶的结构研究
- 批准号:
7597911 - 财政年份:2007
- 资助金额:
$ 0.22万 - 项目类别:
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